Matters of the Heart

“There is the enormous risk one might have to change one’s mind.” Abram Hoffer, M.D.

In spite of advances claimed by conventional medical science, serious human health conditions persist. Research continues, hope is raised, new drugs are approved, and profits are counted. Meanwhile, cardiovascular disease, cancer, diabetes, depression and other mental health issues, Alzheimers, a long list of infectious and food-borne illnesses, disease-causing genetic disorders, and on and on, continue to plague bodies and minds.

According to the World Health Organization, the leading cause of death in the world is heart disease. In 2008 ischemic heart disease accounted for 1/8th of the 57 million deaths worldwide and is increasing in low and middle income countries. Hypertensive heart disease, number 11 on the list, killed 2% of people in that year. Heart disease killed 7.4 million people in 2012 and still is the leading cause of death.

In ischemic heart disease blood flow to the heart is diminished because of a build-up of atherosclerotic plaque in the arteries of the heart. Ischemic heart disease is a major risk factor for congestive heart failure, which has increased steadily over the last 20 years (“Risk Factors for Congestive Heart Failure,” doi: 10.1001/archinte.161.7.996).

So in March and again in August 2014 when Novartis released the results of its PARADIGM-HF study on a new drug for heart disease, it’s no surprise that it attracted considerable attention. The new drug, which was still being investigated and didn’t have a name yet, is designed to target a specific heart condition cardiologists have labeled “heart failure”.

a failure of heart

Heart failure is a type of heart disease in which the heart is unable to pump enough blood to meet the demands of the body. Ischemic heart disease, hypertension, heart attack, and heart muscle or heart valve disease cause or contribute to heart failure; emotional stress, work stress, and other sources of psychosocial stress also are contributors.

Symptoms of heart failure include fatigue, exercise intolerance, heavy breathing, fluid in the lungs (with coughing and wheezing), unusual heart rhythms, difficulty breathing while lying down at night, edema in the ankles and feet, and dizziness.

Conventional medical treatment for heart failure includes medications such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta blockers, calcium channel blockers, statins (HMG-CoA reductase inhibitors), diuretics, lifestyle changes (diet, exercise, smoking cessation) and so on. Sometimes a pacemaker is implanted in the chest. In very serious cases, a heart transplant may be necessary.

In heart failure, energy-producing cells are not getting enough oxygen because the heart is failing in its job to pump oxygenated blood to them. Oxygen induces the production of the energy molecule ATP in a complex chain of reactions in cell structures called mitochondria. Simply stated, oxygen converts glucose into carbon dioxide, water, and the “energy currency” adenosine triphosphate - ATP. In this process energy as ATP is made in all the cells of the human body, including heart muscle cells.

Since nothing happens in the body without ATP, its production is very important. If the heart is unable to pump oxygen-containing blood efficiently to energy-producing cells, every activity in the body will be compromised. The autonomic nervous system will assist the oxygen and energy deficit by increasing the production of adrenalin, which increases blood pressure and respiratory rate. But this is a temporarily useful reaction - this sympathetic reaction of the autonomic nervous system is a feature of the stress response, which is a component in heart failure. Heart muscle cells will work less and less efficiently as adrenal hormones futilely try to make the heart work harder.

Novartis’ new drug, hailed as introducing “a paradigm shift” in heart failure therapy and as representing “a new threshold of hope”, combines an ARB with sacubitril, a neprilysin inhibitor. The ARB is used instead of an ACE inhibitor, according to the study report, due to the latter’s tendency to cause tissue swelling called angioedema, which is a serious side-effect that can be fatal in sensitive patients. Sacubitril, the neprilysin inhibitor, has the effect of increasing concentrations of a heart hormone called atrial natriuretic peptide, which promotes relaxation of blood vessels and inhibits other effects of sympathetic nervous system involvement.

The research compared the new drug to the previous “gold standard” for heart failure, the ACE inhibitor enalapril, which, as mentioned above, can cause angioedema. (In this research, however, though the numbers were small, the group receiving the new drug experienced a higher incidence of angioedema than the enalapril group). According to the study’s authors, the new drug “out-performed” enalapril. Adverse effects, however, were experienced by all test subjects.

heart and kidney, courage and fear

Both ACE inhibitors and ARBs work to lower high blood pressure and hypertension, which are predisposing factors in heart failure. They achieve their effect by acting in a metabolic pathway associated with the kidneys known as the renin-angiotensin system, which is built into the body as a survival mechanism against a loss of blood volume.

The effect of angiotensin, once it gets hooked up at the cell receptor sites, is to increase blood pressure by causing constriction of blood vessels, stimulating aldosterone secretion from the adrenal glands, and increasing sympathetic nervous system activity, among other things. For its part, aldosterone acts on the kidneys to reabsorb sodium and water and, therefore, to increase blood pressure.

Both ACE inhibitors and ARBs lower blood pressure by working in the angiotensin system, but there is a significant difference between the two in how the effect is achieved. ACE inhibitors inhibit the enzyme that converts angiotensin from its inactive form into its active form. If the enzyme isn’t present, the hormone will not become active, aldosterone secretion will not be stimulated, and blood pressure will be modulated. In contrast, ARBs, angiotensin receptor blockers, work at the site of cell receptors after angiotensin has been converted into its active form. With ARBs, though activated angiotensin can’t cause its effect by acting with cells at specific receptor sites, there remains in the blood a significant amount of activated angiotensin. Though ARBs lower blood pressure, the active angiotensin in blood has side-effects by acting through secondary receptors.

ARBs are very specific about the receptors they block. Activated angiotensin, while not interacting with its primary receptor, will continue to interact with receptors of a secondary but supportive role. Researchers have discovered several activated angiotensin receptor sites on tissue cells only one of which is blocked by the ARB in Novartis’ LCZ696. In relation to this and in spite of the fact that ARBs performed well at lowering blood pressure, a “paradoxical” effect has been observed: in other studies ARBs were associated with an increase in heart attacks and other cardiovascular events (doi: 10.1161.CIRCULATIONAHA.105.594986). This unwanted effect of ARBs has called into question the drug’s usefulness in the treatment of heart failure and explains why they’re not prescribed as a first line drug for the condition.

The other component of Novartis’ LCZ696 is the neprilysin inhibitor, sacubitril. Neprilysin is an important enzyme that breaks down proteins that tend to cause vasodilation among other things. The net effect of inhibiting neprilysin, therefore, is vasodilation, which is beneficial to people with high blood pressure.

One of the proteins degraded by neprilysin is atrial natriuretic peptide (ANP), a potent vasodilator secreted by cardiac muscle cells of the atria of the heart. Having the opposite effect of the adrenal hormone aldosterone, ANP helps to reduce blood pressure by causing sodium and water excretion by the kidneys. (A co-principle investigator in the trial said that the neprilysin inhibitor “enhances the body’s natural defenses against heart failure”, artificially stretching the definition of “natural” into a convenient distortion.) ANP secretion is increased naturally by a number of things including exercise and immersion in water.

In rats, however, artificial neprilysin inhibition is associated with an increase of proteins in the brain that are related to Alzheimer’s disease (“Identification of the major AB1-42 degrading catabolic pathway in brain parenchyma: Suppression leads to biochemical and pathological deposition,” Nature Medicine 2000; doi: 10.1038/72237). That is, neprilysin is an enzyme that degrades the proteins associated with Alzheimer’s disease. Therefore, artificial neprilysin inhibition may be useful against heart disease but also may contribute to an increase in Alzheimer’s in humans.

In any case, PARADIGM-HF, Novartis’ double-blind trial involving over 8000 patients, appears well designed and executed and the results seem to demonstrate the superiority of LCZ696 over the previous “gold standard” drug, the ACE inhibitor enalapril. The original article “Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure” (doi: 10.1056/NEJMoa1409077) can be viewed at nejm.org.

cross my heart

A correct diagnosis of heart failure is not an easy one to make. There is no definitive diagnostic rubric, there are many classifications and categories, and there are other serious illnesses causally related to heart failure.

An article titled “Heart Failure: Gaps in Knowledge and Failures in Treatment” by Druin Burch, published on plosmedicine.org in August 2014 (doi: 10.1371/journal.pmed.1001702) cites some of the problems in the diagnosis and treatment of heart failure. The author paraphrases the conclusion of a cited article: ...“routinely doctors and healthcare systems cause needless death and major illness through failing to provide the care they should”. Burch continues,

Recent work has suggested that 85% of all medical research is wasted through asking the wrong questions or asking questions badly, and more through difficulties in open access to useful knowledge. Still more, though, is wasted when valuable and widely disseminated research results are not acted on.

Geographical discrepancies in the diagnosis and treatment of heart failure suggest that clinical opinions and behaviour vary across the world. One speculation is that clinical diagnoses of heart failure are often plain wrong.

For some patients diagnosed with heart failure based on clinical evaluation, care “...is typically limited to efforts to relieve symptoms…” because “ …no treatments have been shown to improve outcomes…” (“Lessons from TOPCAT Trial”, New England Journal of Medicine, April 2014; doi: 10.1056/NEJMe1401231).

Medical drug research is plagued with a unique set of problems and pressures.

According to “Why Most Published Research Findings Are False” written in 2005 (doi: 10.1371/journal.pmed.0020124) by John Ioannadis, M.D., medical research has issues:

There is increasing concern that in modern research, false findings may be the majority or even the vast majority of published research claims. However, this should not be surprising. It can be proven that most claimed research findings are false.

Published research findings are sometimes refuted by subsequent evidence...

Conflicts of interest are very common in biomedical research, and typically they are inadequately and sparsely reported. Prejudice may not necessarily have financial roots. Scientists in a given field may be prejudiced purely because of their belief in a scientific theory or commitment to their own findings.

Prestigious investigators may suppress via the peer review process the appearance and dissemination of findings that refute their findings, thus condemning their field to perpetuate false dogma. Empirical evidence on expert opinion shows that it is extremely unreliable.

...the fact that a field is hot or has strong invested interests may sometimes promote larger studies and improved standards of research, enhancing the predictive value of its research findings...

Traditionally investigators have viewed large and highly significant effects with excitement, as signs of important discoveries. Too large and too highly significant effects may actually be more likely to be signs of large bias in most fields of modern research.

As for the intentional manipulation of data in research, Ioannidis says, "Commercially available "data mining" packages actually are proud of their ability to yield statistically significant results through data dredging."

In reference to other research trials, Ioannidis says, “Early termination of... trials owing to statistically significant interim analyses inflates estimates of treatment effects.” The “selection of high risk populations” also inflates a test drug’s effects (BMJ 2013; 347:f6698).

PARADIGM-HF, funded by Novartis, was terminated early. It was a large trial involving “high risk populations”, hundreds of doctors from dozens of countries, and resulted in “highly significant effects”.

Ioannidis “...has become one of the world’s foremost experts on the credibility of medical research. He and his team have shown, again and again, and in different ways, that much of what biomedical researchers conclude in published studies… is misleading, exaggerated, and often flat-out wrong. He charges that as much as 90 percent of the published medical information that doctors rely on is flawed.” Yet “his work has been widely accepted by the medical community…” However, he doubts that change in medical research will come easily. According to “Lies, Damned Lies, and Medical Science” by David Freedman, Ioannidis fears that “pervasive flaws” and “conflicts of interest” will inhibit necessary changes (TheAtlantic.com/magazine/archive/2010/11/lies, damned lies/308269).

There is an intellectual conflict of interest that pressures researchers to find whatever it is that is most likely to get them funded.

Ioannidis believes that the peer-review process itself may encourage researchers to stick with the herd because their colleagues, members of the herd, are the ones performing the review. In this way wrong outcomes may be repeated and new ideas avoided. He says,

I’m not sure that more than a very small percentage of medical research is ever likely to lead to major improvements in clinical outcomes and quality of life. We should be very comfortable with that fact.

Nor is it likely that this insight will be repeated by pharmaceutical industry spokespeople.

Still some critics of the system who have seen it up close are unwilling to make any assumptions about the efficacy of medical practice. A 2006 businessweek.com article features cardiologist turned mathematician David Eddy, M.D., Ph.D., who created a computer program that he says determines an effective and efficient treatment plan given a specific diagnosis. He says,

The problem is we don’t know what we’re doing… The practice of medicine is more guesswork than science… The limitation is the human mind.”

Dr. Eddy calls his computer program “Archimedes” after the great Ancient Greek mathematician. Compare Dr. Eddy’s approach to that of Dr. Abram Hoffer’s, which is revealed in his recommendation: “We have to learn to think rather than calculate.”

shot through the heart

For all the logic and rigor to which it ascribes its activity, conventional medical drug research is a kind of high stakes wild-goose chase for an elusive ultimate destructive projectile: the magic bullet. “Magic bullet” is a metaphor for a chemical substance that could be injected into, or swallowed by, a patient that would destroy an offending agent, infectious organism, or cancer and leave the rest of the body unaffected. “Magic bullet” was coined and defined by 19th century German physician Paul Ehrlich.

Ironically, there’s an old German folktale about a young man who makes a deal with the devil for a “magic bullet” to be used in a contest of marksmanship to win the love of a young woman. The tale, which was made into an opera in the mid 19th century, became popular throughout Europe. This opera was considered culturally important in Germany in that period.

Ehrlich’s “magic bullet” concept grew out of the aggressive “heroic medicine” practices of the early 19th century. His invention of the arsenic compound salvarsan (considered the first chemotherapeutic agent) for the treatment of syphilis gave him mild success in the idea’s realization. Though it was effective, salvarsan had serious harmful side effects.

The “magic bullet” idea still dominates drug research. The related concept of a “biological target”, denoting an enzyme, hormone receptor, cell membrane protein, nucleic acid, and so on, that can be altered by a chemical drug (the “magic bullet”) for a specific therapeutic effect, is the modus operandi of so-called drug discovery in the pharmaceutical industry. A Therapeutic Target Database that contains 2025 targets and 17,816 magic bullet drugs is available “for facilitating drug discovery” (http://bidd.nus.edu.sg/group/cjttd/TTD.asp).

Ehrlich was a colleague of Robert Koch whose “Postulates” and “germ theory” became the foundation of bacteriology. Famous French chemist Louis Pasteur, British surgeon Joseph Lister, German physician Hermann von Helmholtz, and French physiologist Claude Bernard, among others, were responsible for important advances in 19th century science and medicine, or so we’re told. This post “heroic medicine” era, in which chemical research was applied increasingly to medical conditions, called the attention of American education reformers to the educational systems within which these advances came about.

In the late 19th century, European and especially the German (or Prussian, as it was called) educational system became the model for the standardized public and university education systems in America. Horace Mann, Henry Pritchett, Daniel Coit Gilman, Charles Eliot, and others imported and implemented the German system, and became influential in defining public, university, and postgraduate education in the U.S. Pritchett, who earned a Ph.D. at the University of Munich, was president of Massachusetts Institute of Technology and president of the Carnegie Foundation when Abraham Flexner wrote his report on medical education in the U.S.; Gilman, who was president of University of California and Johns Hopkins University, and a founder of Carnegie Institute, made it his personal policy to remodel American universities on the German system; and Eliot, president of Harvard, visited European schools and was impressed that they used discoveries of scientific principles to promote the development of industry.

The magic bullet-biological target concept of chemical medicine is expressed repeatedly in the pharmaceutical industry’s attempts to invent drugs to “combat” and to “wage war” on fearsome human health conditions. In the case of Novartis’ PARADIGM-HF, magic bullet LCZ696 targets an angiotensin receptor and blocks it, and targets the enzyme neprilysin, which it inhibits. This metaphor betrays a perceptual mode conditioned by training, education, and culture that is increasingly difficult to maintain because cultural values are changing.

The bullet-target concept is based in the reductionist philosophy that complex systems are mechanical and can be broken down into smaller units without distortion or compromise. This perception empowered scientists in the 19th century in the study of the human “machine” and its “mechanisms”. The reductionist philosophy was expressed succinctly by Hermann von Helmholtz in the late 19th century who said, as a way of trying to eliminate “vital forces” from the scientific equation, “...no other forces than the common physical-chemical ones are active within the organism.” This reductionist philosophy facilitated the industrial revolution.

That a natural physiological process has an immediate cause that can be targeted and blocked or inhibited by a specific chemical agent, which will have no other significant effect in the human body, is an assumption of conventional medical science and of pharmaceutical research in particular. This assumption, for the most part, is one we must swallow along with our prescription, pharmaceutical medicine.This assumption, which is rooted in the mechanical perception, will be scrutinized, re-evaluated, and abandoned increasingly as holistic models of human function are validated increasingly.

heart to heart

A press release on the European Society of Cardiology’s website dated May 25, 2013, in conjunction with the annual meeting of the Heart Failure Association of the European Society of Cardiology, highlighting the results of a CoQ10 research project, is titled “A potential new approach to improve heart failure outcome - Coenzyme Q10 decreases all cause mortality by half in randomised double blind trial”. Lead author Svend Mortensen of Denmark says in the article,

CoQ10 is the first new medication to improve survival in chronic heart failure and it should be added to standard therapy…. Other heart failure medications block rather than enhance cellular processes and may have side effects. Supplementation with CoQ10, which is a natural and safe substance, corrects a deficiency in the body and blocks the vicious metabolic cycle in chronic heart failure called the energy starved heart.

Of course Mortensen’s CoQ10 research is subject to the same criticisms as Novartis’ PARADIGM-HF (Mortensen is affiliated with a company that manufactures CoQ10) but there are important differences: CoQ10 is safe, it’s produced endogenously in the body, it’s an antioxidant and a cofactor in the electron transport chain, it’s normally in high concentrations in the heart and kidneys, it prevents oxidation of bad cholesterol, and is known to be deficient in degenerative diseases. Plus, it’s been studied and recommended as a dietary supplement for about 50 years.

In the introduction to a December 2014 article in the journal Clinical Pharmacology and Therapeutics (doi: 10.1038/clpt.2014.175), Mortensen continues,

Heart failure is a disabling disease with increasing prevalence and a poor prognosis despite advances in drug and device-based therapies. The biochemical rationale for using Q10 (CoQ10) in HF is correction of a deficiency state whose association with the disease was established years ago.

CoQ10, also known as ubiquinone, because in the body it is a ubiquitous quinone (a class of chemicals based on a ring structure), was discovered in 1955. The specific structure of CoQ10 was identified in 1958 by Merck pharmaceutical chemist Karl Folkers who also determined the chemical structures of vitamin B-6, pantothenic acid, biotin, vitamin B-12, and lipoid acid, among other things. Folders promoted the therapeutic value of CoQ10 and recommended its use, but his rationale fell on deaf ears. In 1990 Folkers and others (pas.org/content/87/22/8928.full.pdf) found that

lovastatin does indeed lower tissue concentrations of CoQ and that a return to normal can be achieved by supplementation with CoQ.

Karl Folkers was one of the more important 20th century researchers in biochemical nutrition.

losing heart

Merck manufactures the HMG-CoA reductase inhibitor lovastatin and sells it under the name Mevacor. Lovastatin is prescribed to lower cholesterol, which is the very important precursor for all steroid hormones, vitamin D, and bile in the human body. Lovastatin can have many side effects including muscle aches and pain, gastrointestinal upset, dizziness, weakness, liver damage, memory loss, confusion and, notably, increased blood serum levels of creatine phosphokinase. Creatine phosphokinase (also called creatine kinase), is the enzyme, especially important in heart muscle, that transfers a phosphorous group to ADP to maintain ATP levels when the heart is under high demand. Increased creatine phosphokinase found in blood tests is an indication of tissue damage. Heart tissue creatine phosphokinase is depleted in heart failure.

CoQ10 is made in the human body in the same biosynthetic pathway in which cholesterol is made. The enzyme that controls the rate of production of cholesterol, CoQ10, and other important substances in this pathway is called HMG-CoA reductase - the biological target for the magic bullet statin. CoQ10 production is inhibited also by beta blockers, pharmaceutical bullets that target the action of some adrenal hormones in hypertension and other cardiovascular conditions.

Paradoxically, it begins to seem as if the treatment of heart disease with prescription drugs creates conditions that cause or contribute to... heart disease.

Some papers indicate that CoQ10 depletion during statin therapy might be associated with subclinical cardiomyopathy and this situation is reversed upon CoQ10 treatment. ("The Role of CoenzymeQ in Cellular Medicine," Mitochondrion 2007, doi: 10.1016/j.mito.2007.03.002).

This “statin cardiomyopathy” has been implicated as a causal factor in the development of heart failure, the incidence of which has been increasing since the introduction of statins.

...statin-related side-effects, including statin cardiomyopathy, are far more common that previously published and are reversible with the combination of statin discontinuation and supplemental CoQ(10). We saw no adverse consequences from statin discontinuation. (PMID: 16873939).

Statin drugs, prescribed to reduce cholesterol, actually cause an up-regulation of the process by which cholesterol is made (“Quercetin up-regulates LDL Receptor…”, Physiotherapy Research, March 2012, doi: 10.1002/ptr.4646). This discovery has led drug companies to develop monoclonal antibodies to potentiate the effects of statins by inhibiting an enzyme identified as PCSK9 which prevents LDL clearance from blood at cell receptor sites. This research shows that the naturally-occurring bioflavonoid quercetin, found in fruits and vegetables and as a nutritional supplement, increases cell LDL receptors and inhibits PCSK9 resulting in lower serum LDL. Quercetin also reduces oxidized vitamin C as a way of recycling it for subsequent antioxidant activity.

An article in Trends in Biochemical Science by Costet, and others, titled “PCSK9 and LDL Cholesterol: Unravelling the Target to Design the Bullet,” demonstrates that the conventional perceptual mode has been carried forward into medical science’s latest whack-a-mole extravasation (doi: 10.1016/j.tibs.2008.06.005).

CoQ10 depletion is not the only potentially harmful side effect of statin therapy intended to lower cholesterol by targeting HMG-CoA reductase. Because so many important molecules are made in this pathway (called the mevalonate pathway) a wide range of adverse effects may become apparent from inhibition of this one enzyme. An August 2010 Scientific American article titled “It’s Not Dementia, It’s Your Heart Medication: Cholesterol Drugs and Memory” is a personal report on the cognitive side effects of statins experienced while taking them as prescribed. Though there is some equivocation in the article about these adverse effects, one statin patient, Duane Graveline, M.D., expresses a more definitive opinion on his website www.spacedoc.com. Graveline says certain statins’ adverse side effects such as sleep disturbances, nightmares, memory loss, depression, and interstitial lung disease are generally acknowledged and serious, and patients should be warned of them.

An article titled “Atorvastatin-associated Memory Loss: Analysis of 662 Cases of Cognitive Damage Reported to Medwatch” by Graveline and Cohen that appears on Graveline’s website ends with the paranoia-inducing statement: “There is resonable research evidence that 100% of statin users suffer some cognitive deficit that is not evident to them.”

An article in the December 2014 JAMA Internal Medicine titled “Statin-Related Cognitive Impairment in the Real World - You’ll Live Longer but You Might Not Like It”, written by non-medical professional Jonathan McDonagh (doi: 10.1001/jamainternmed.2014.5376), discusses the authors experience with statin drugs. McDonagh says that after he had not taken his statin medication for a few days he realized that they were making him grumpy, depressed, and mentally slow when he did take them as prescribed. He tells of the trouble he had convincing his doctor that statins were causing these problems, and the relief he experienced when he quit taking them.

It’s disappointing to miss out on some of the cardiovascular benefits that statins may provide. But it’s more important to me to have my cognitive function back so I can earn a living and provide for the people I love.

Apparently, Mr. McDonagh had been sold on statins’ “cardiovascular benefits”.

Cholesterol is the most common organic molecule in the brain and is essential to neurological function. Non-neuronal brain cells called glia produce cholesterol for their growth and survival. In a 2001 report in Science (“CNS synaptogenesis promoted by glia-derived cholesterol,” Pub Med I.D. 11701931), Mauch and others announced their discovery about the “synapse”, which facilitates the transmission of electrical signals between neurons or between a neuron and a receptor cell:

Previous reports showed that a glia-derived factor strongly promotes synapse development in cultures of purified CNS neurons. Here, we identify this factor as cholesterol… CNS neurons produce enough cholesterol to survive and grow, but the formation of numerous mature synapses demands additional amounts that must be provided by glia. Thus, the availability of cholesterol appears to limit synapse development. 

A review of the importance of cholesterol in synapse formation titled “Role of cholesterol in synapse formation and function” by F. Pfrieger (doi: 10.1016/s0005-2736(03)00024-5) concludes,

Cholesterol is an essential component of synapses and… their formation, function, and stability are sensitive to disturbances in cholesterol metabolism.

As for other effects of lowering cholesterol (“The Ugly Side of Statins. Systemic appraisal of the Contemporary Unknown Unknowns”, in The Open Journal of Endocrine and Metabolic Disease, doi: 10.4236/ojemd.2013.33025) considerable controversy persists:

We seem to have fallen into the marketing trap and ignored the niggling side effects with regard to the HMGCoA reductase inhibitors. The only statin benefit that has actually been demonstrated is in middle aged men with coronary heart disease. However, statins were not shown to best form of primary prevention. Aspirin, as a form of primary prevention decreases the risk for total cardiovascular events and nonfatal Myocardial Infarction over any other factor. In actual fact, high cholesterol levels have been found to be protective in elderly and heart failure patients and hypo-cholestereamic patients had higher incidence of intra-cerebral bleeds, depression, and cancer.

The statin industry, with all of its spin-off, is a 20-billion-a-year industry. We are observing the revealing of the utmost medical tragedy of all times. It is unprecedented that the healthcare industry has inadvertently induced life-threatening nutrient deficiency in millions of otherwise healthy people. What is even more disparaging is that not only has there been a failure to report on these negative side-effects of statins, there has actually been active discouragement to publish any negative studies on statins. 

Statins... induce insulin resistance..Cholesterol is a critical component of neuronal cell membranes and synapses, and plays an important role in their proper functioning. A strong association between lower cholesterol and Parkinson disease risk has been reported... 

Cholesterol levels are the main determinant of coenzyme Q10, an important antioxidant and mitochondrial electron receptor. Coenzyme Q10 is neuroprotective and in study involving patients with early Parkinson disease, administration of high-dosage (1200 mg/day) coenzyme Q10 significantly slowed progression of disability with halting of their statin. 

The Confirm registry had shocked the scientific world with the strongest evidence that statin use is associated with an increased prevalence and extent of coronary plaques calcification. Ironically for a drug which was marketed to lower the risk of cardiovascular disease, the confirm registry identified a strong association of statin use to the progression of coronary artery plaque features. 

Statin use was correlated with a greater incidence of severe coronary artery stenosis... 

Statin therapy activates Atrogen-1 Gene which results in muscle atrophy, wasting and damage... statin induced cardiomyopathy is the result of statin-induced coenzyme q10 deficiency and statin-induced atogen-1 activation. 

There is increased risk of Diabetes Mellitus, Cataract formation, and Erectile Dysfunction in young statin users... there is a significant increase in the risk of cancer and neurodegenerative disorders in the elderly plus and enhanced risk of a myriad of infectious diseases. 

All side effects are dose dependent and persist during treatment. 

Statin therapy activates Atrogen-1 Gene which results in muscle atrophy, wasting and damage... statin induced cardiomyopathy is the result of statin-induced coenzyme q10 deficiency and statin-induced atropine-1 activation. 

There is increased risk of Diabetes Mellitus, Cataract formation, Erectie Dysfunction in young statin users... there is a significant increase in the risk of cancer and neurodegenerative disorders in the elderly plus an enhanced risk of a myriad of infectious diseases.

All side effects are dose dependent and persist during treatment. 

Obviously punches were not pulled in this non peer-reviewed article. The "Confirm registry" mentioned is in reference to this discovery: "Statin use is associated with an increased prevalence and extent of coronary plaques possessing calcium." (Statin use and coronary artery plaque composition: Results from the International Multicenter CONFIRM Registry", doi: 10.1016/j.atherosclerosis.2012.08.002).

Another comprehensive look at statin adverse effects (AE) by Golomb and Evans (“Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism” in American Journal of Cardiovascular Drugs… 2008;8(6):373-418) reveals that “[P]hysician awareness of statin AEs is reportedly low even for the AEs most widely reported by patients.” The article concludes, “[S]tatins are a linchpin of current approaches to cardiovascular protection: however, AEs of statins are neither vanishingly rare nor of trivial impact.”

hungry heart

The theory that heart failure is the result of a depletion of cofactors or raw materials necessary to make energy in heart muscle cells has been a consideration since the late 1920’s. That is, is the failing heart “energy starved”? In 1933 Dechard and Visscher determined that “the failing heart is not in need of fuel, but rather of materials for repairs…” (“The failing heart is unable to convert… energy into useful work.” PubMed id: 19870240.)

A more recent review exploring the hypothesis of an energy-starved failing heart uncovered several interesting facts including: 1) production of the “energy” molecule adenosine triphosphate (ATP), which is critical to the normal function of the heart, decreases slowly in heart failure; 2) creatine and the phosphocreatine/creatine kinase shuttle, which is responsible for the rapid formation of ATP during times of cardiac stress, decrease significantly in heart failure; 3) energy production shifts from using fatty acids (oxidative phosphorylation) to glucose (glycolysis); 4) production of new adenine, a component of the ATP molecule, is reduced (“Is the failing heart energy starved”, Circulation Research, 2004. doi 10.1161/01.res.0000137170.41939.d9). Supplementing the diets of heart failure patients with creatine or adenine had only “modest” success, however, according to this article.

by heart

One of the more researched and least recognized nutrients for its importance in the human diet, especially as it relates to heart function, is magnesium (Mg). In 1933 Wilkins and Cullen found in human cadavers that “...hearts showing cardiac disease have a decidedly lower magnesium content than do the normal hearts.” (J. Biol. Chem. 1933 102: 415-423.)

In 1959, exploring the relationship between steroid-induced heart lesions and electrolytes in rats, duRuisseau and Mori reported in “Biochemical Studies on Experimental Cardiomyopathy” (Br J Exp Pathol. v. 40(3); 1959 Jun) that

...it is established that the feeding of K- or Mg- deficient diets results in cardiac necrosis.

...if either MgCl or KCl is administered simultaneously with phosphate-steroid treatment no cardiac necrosis can be detected.

Subsequently, they found that potassium (K) was unchanged but magnesium (Mg) “dropped considerably” under experimental steroid-treatment conditions.

Mg deficiency can cause secondary K depletion, Na retention and hypercalcemia in rats… due to a Mg deficiency in mitochondria. Mg plays a role of primary importance amongst electrolytes in relation to metabolism of living tissues.

An article in the American Journal of Clinical Nutrition (1987;45:1305-12) by P.O. Wester, M.D., titled “Magnesium”, says

...magnesium deficiency was first observed in cattle (grass staggers). The symptoms (irritability, excitation, exhaustion, fibrillary fasciculations, muscle cramps, tetany, etc.) could be relieved by feeding the animals Mg supplements. Autopsy examination of cows and calves who died revealed severe cardiovascular damage including necroses and calcification. Experimental Mg deficiency in rats produces degenerative changes in skeletal and cardiac muscle and renal tubular changes with nephrocalcinosis.

Mg deficiency in man may develop in many disease states. Symptoms may come from the central nervous system, the skeletal muscles, the gastrointestinal tract, and the cardiovascular system. The symptoms are often vague and uncharacteristic in mild deficiency.

Dietary Mg deficiency tends to produce cardiovascular damage in experimental and domestic animals and hypertension as well as hyperlipidemia has been observed in Mg-deficient animals. There is also some evidence from epidemiological data that Mg might be involved in cardiovascular disease.

Researcher Mildred Seelig, M.D.’s contribution to our understanding of the importance of magnesium in human physiology is extraordinary and yet relatively unknown. A review of her books and published articles, available at the Magnesium Online Library (www.mgwater.com), verifies her authority. Her 1980 book Magnesium Deficiency in the Pathogenesis of Disease provides exhaustive evidence that magnesium deficiency or insufficiency causes or contributes to heart attack, arrhythmias, atherosclerosis, infant sudden death, and other diseases. In her 2003 The Magnesium Factor with Andrea Rosanoff, Ph.D., Dr. Seelig outlines in layman’s language the importance of magnesium in the human diet and the diseases caused by magnesium deficiency. “The solution to heart disease has been with us all along, and it is nutritional. Most modern heart disease is caused by magnesium deficiency.”

From Dr. Seelig’s “Cardiovascular Consequences of Mg Deficiency”:

Dietary magnesium (Mg) deficiency is more prevalent than generally suspected, and can cause cardiovascular lesions leading to disease at all stages of life. The average American diet is deficient in Mg, especially in the young, in alcoholic persons, and in those under stress or with diseases or receiving certain drug therapies, who have increased Mg needs. Otherwise normal, Mg deficient diets cause arterial and myocardial lesions in all animals, and diets that are atherogenic, thrombogenic and cardiovasopathic, as well as Mg-deficient, intensify the cardiovascular lesions, whereas Mg supplementation prevents them. Diuretics and digitalis can intensify an underlying Mg deficiency, leading to cardiac arrhythmias that are refractory unless Mg is added to the regimen. Potassium (K) depletion in diuretic-treated hypertensive has been linked to an increased incidence of ventricular ectopy and sudden death. K supplementation alone is not the answer. Mg has been found to be necessary to intracellular K repletion in these patients. Because patients with congestive heart failure and others receiving diuretic therapy are also prone to chloride loss, leading to metabolic alkalosis that also interferes with K repletion, the addition of Mg and Cl supplements in addition to the K seems prudent.

A variety of stresses, both psychological and physical, increase Mg requirements and cause increased cellular Mg loss.

A vicious cycle can... develop, because exogenous or endogenous catecholamines secreted as a result of stress cause mobilization of cellular Mg, particularly from the myocardium - from which 12-39% losses have been reported, in association with uptake of Ca. The loss of myocardial Mg precedes cardiac damage and Ca accumulation. It has been postulated that catecholamines also block Mg ingress across a proposed Mg-channel.

Mg modulates Ca uptake by myocardial mitochondria, thereby protecting against conditions and drugs that increase Ca ingress and damage to the heart. The lesions of the mitochondria of the heart caused by Mg deficiency resemble those of myocardial ischemia and of catecholamine induced cardiopathy; in experimental models, and in fatal clinical ischemic heart disease, the first alteration is loss of Mg from the heart.

The most arrhythmogenic disease, congestive heart failure, is responsible for many unexpected sudden deaths - not from progressive circulatory failure, but suddenly and unexpectedly, at a rate even higher than among patients in the first 12 months after myocardial infarction. This has been attributed to the dysrhythmias caused by the electrolyte disturbances produced both by compensatory mechanisms and by treatment of the disease.

The compensatory mechanisms resulting from reduced cardiac output cause increased secretion of vasoconstrictor and volume regulating hormones: catecholamines, renin-angiotensin-aldosterone, and anti-diuretics. Catecholamine and aldosterone secretion is increased by underlying Mg deficiency - which is increased by both diuretic and digitalis therapy, which further stimulate the neurohormones. Loss of K and Mg, caused by diuretics and aldosterone, increases arrhythmias, which are intensified by angiotensin's stimulation of aldosterone secretion and potentiation of the sympathetic nervous system.

Correction of secondary aldosterone- and treatment-induced losses of both K and Mg is responsible for the favorable immediate response of heart failure patients with digitalis arrhythmias. When both cations are deficient, repletion of Mg is necessary for the repair of Mg and K tissue levels and the dysrhythmias. Infusion of K before Mg infusion had a much weaker anti-arrhythmic effect than did Mg infusion alone; in several patients, the K infusion actually caused more ectopic beats, that were largely corrected by the Mg infusion.

The Magnesium Online Library contains a wealth of material about dietary magnesium deficiency written by Dr. Seelig.

One wonders why this research has not made its way into the conventional medical establishment or, if it has, why it is being ignored. Cardiologist James Roberts, M.D. proposes an answer:

...politics, money, and training. Major medical research is funded by drug companies… Nutritional therapies do not move the revenue needle for hospitals, doctors, research institutions, or the drug companies. And… doctors have not been well trained in biochemistry….

...doctors do not want to be known as “vitamin doctors.”

...they use the “lack of science” argument when discussing nutritional therapies.

The orthodox medical community is ten years behind in this area of research…

Nutritional science provides answers to many lingering questions in medicine. It’s the difference between natural science and the man-made science of drug therapy.

Dr. Robert’s comments appear in the Introduction to The Sinatra Solution: Metabolic Cardiology by Stephen Sinatra, M.D. Dr. Sinatra’s “Solution” includes dietary supplementation with CoQ10, magnesium, ribose (the five-carbon sugar found in ATP), and carnitine.

Carnitine is an amino acid-like metabolite made in the human body from the two essential amino acids methionine and lysine. Carnitine is important as a transporter of long chain fatty acids into the mitochondria of cells where they can be used to produce energy in the form of ATP.

The March 1990 American Journal of Cardiology contains an article titled "Defective myocardial carnitine metabolism in congestive heart failure secondary to dilated cardiomyopathy and to coronary, hypertensive and valvular heart diseases" (doi: 10.1016/0002-9149(90)91383-H) says

...total myocardial carnitine was significantly reduced in patients with dilated cardiomyopathy... and CHF.... Alterations in myocardial caritine metabolism represent nonspecific biochemical markers in CHF with yet unknown consequences for myocardial function.

Reduced myocardial carnitine may result in reduced oxidation of fatty acids for energy production and a reversion to glucose metabolism in glycolysis, which, as noted above, is the case in heart failure.

Carnitine is most abundant in heart and skeletal muscle. Because of heart muscle’s occasionally increased requirement for energy, and carnitine’s function as a cofactor in the metabolism of fatty acids to make eneregy, carnitine has been studied as a treatment in heart failure. The conclusion of one study (Pub Med ID10650325) reads: “L-carnitine appears to possess considerable potential for the long-term treatment of patients with heart failure attributable to dilated cardiomyopathy.”

have a heart

Linus Pauling, Ph.D.’s ascorbic acid research and promotion as a cure for cardiovascular disease is based on the observation that the disease is a form of scurvy. Eventually, Pauling added the amino acid lysine to his high-dose ascorbic acid protocol, which became known as “Pauling Therapy”. It was Pauling’s contention that lysine inhibits and even reverses the build-up of atherosclerotic plaque, which is the predisposing factor in cardiovascular disease. And, as mentioned above, lysine is one of two essential amino acids required in the endogenous production of carnitine. Pauling believed that his protocol could “...control cardiovascular disease, heart attacks and strokes…” and even cure it. (www.paulingtherapy.com).

Pauling and colleague Matthias Rath, M.D., developed the “Unified Theory of Human Cardiovascular Disease” in 1989. Their scientific paper on the subject, “A Unified Theory of Human Cardiovascular Disease Leading the Way to the Abolition of This Disease as a Cause for Human Mortality,” initially was accepted for publication by the National Academy of Sciences but was never published (www.paulingtherapy.com). In spite of the fact that there is abundant research that supports Pauling’s hypothesis, it has not been tested.

In 1985 a paper published in The Journal of Biological Chemistry titled “Inhibition of Human Leukocyte 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase Activity by Ascorbic Acid”, by Harwood and others, exploring the hypothesis “...that marginal ascorbate deficiency may be a significant contributing factor to development of hypercholesterolemia and atherosclerosis in man,” found that ascorbic acid “...may be important in the regulation of endogenous cholesterol synthesis in man.” This paper proposes that ascorbic acid lowers cholesterol and modulates its synthesis in the body by decreasing the activity of HMG-CoA reductase non-competitively and that, reciprocally, low vitamin C causes HMG-CoA reductase to increase its activity, thus increasing cholesterol synthesis. Article authors propose that as much as a 50% inhibition of human leukocyte HMG-CoA reductase is possible with ascorbic acid, based on their model. They discovered further that ascorbic acid’s ability to act on HMG-CoA reductase is potentiated by endogenous glutathione, and that ascorbic acid promotes the biosynthesis of CoQ10.

Most animals produce ascorbic acid endogenously. A few animals, including some apes, the guinea pig, a kind of bat, and humans, do not. Cardiovascular disease occurs only in the animals that do not have endogenous production of ascorbic acid. Authorities say that an animal that weighs 150 lbs biosynthesizes 12 to 13 grams of ascorbic acid daily, and more when stressed.

As good as it was, Pauling’s theory concerning heart disease, and his and Rath’s “Unified Theory” paper did not appear at a good time. By then Merck was marketing its lovastatin Mevacor, the “lipid hypothesis” of heart disease had become established (though still controversial), and the National Heart, Lung, and Blood Institute’s “1984 Coronary Primary Prevention Trial” was published in the Journal of the American Medical Association (doi: 10.1001/jama.1984.03340270029025) purportedly demonstrating the heart health benefits of lowering blood cholesterol. (The substance used in this study was not a statin, however, but the drug cholestyramine that binds bile in the intestine for excretion.)

In the mid 1960’s the National Heart, Lung and Blood Institute, a division of the National Institutes of Health, began exploring the development of a “permanently implantable artificial heart to replace the ailing natural heart.” This seems a macabre idea but the bioengineers believed they could design mechanical pumps and control systems to do what the natural heart does. The first “successful” heart transplant was performed in 1982 on a dentist with heart failure. He lived for 112 days but with additional surgeries, complications from bleeding, and mental confusion. He asked to die on several occasions (celebrities.healthdiaries.com). Wikipedia says that “A synthetic replacement for the heart remains one of the long-sought ‘holy grails’ of modern medicine.”

openhearted

Canadian psychiatrist Abram Hoffer, M.D., who used large doses of niacin in his treatment of schizophrenia and alcoholism, discovered that the vitamin also had a beneficial effect on blood cholesterol: it lowered total cholesterol and raised HDL, the “good” cholesterol. In the 1980’s the Mayo Clinic confirmed niacin’s beneficial effect and it was approved by the FDA for the treatment of hypercholesterolemia.

Before earning a medical degree, Hoffer was a biochemist studying the niacin content in wheat. But he abandoned agricultural research after developing an interest in medicine and eventually in psychosomatic medicine and psychiatry. In the early 1950’s, Hoffer realised his ideal: combining biochemistry and psychiatry in research.

By 1952 Hoffer identified schizophrenia as “the most important single problem”. Half of mental hospital beds in Canada, he said, were occupied by schizophrenics, and one quarter of all hospital beds in the country at that time were occupied by schizophrenics. As a doctor with a background in biochemistry, especially in niacin and the other B vitamins, it was natural for Hoffer to explore the biological basis of this disease. Unfortunately, psychoanalysis and other forms of “talk” therapy had become very popular in psychiatry, making it difficult for Dr. Hoffer and colleagues to communicate their discoveries.

Dr. Hoffer’s research into the effects of adrenal hormones on cognitive function is especially important. He found that the oxidized form of adrenalin, adrenochrome, and related neuro-hormones, possess psychoactive properties and could cause hallucinations and psychoses. Known as the “Adrenochrome Theory of Schizophrenia” Dr. Hoffer explained it this way:

...schizophrenia arose in an individual when too much adrenochrome was formed, that adrenochrome then interfered with brain function as would LSD, and that created the essential stage for the formation of schizophrenia.

Not only is adrenochrome toxic to neurons, Hoffer demonstrated its toxicity to heart tissue:

Adrenochrome is toxic to myocardial tissue and may be responsible for fibrillation and sudden death under stress. Myocardial tissue is very high in the enzyme which oxidizes adrenalin to adrenochrome.

He discovered that ascorbic acid and glutathione can reduce, that is, neutralize adrenochrome. Dr. Hoffer recommended that people with Parkinson’s disease take niacin because “...it protects brain tissue against some of the toxic effects of adrenochrome…” and that “niacin could prevent the excessive formation of adrenochrome on myocardial tissue…”

(From “Dopamine, Noradrenalin and Adrenalin Metabolism…” 1985, by Abram Hoffer, M.D.-Ph.D at orthomolecular.org).

The aminochromes undoubtedly are involved in almost every reaction in which catecholamines play a part. A vast new area has now opened for physiological and bio-chemical research. Thus, Ganguly (1989) and Ganguly, Beamish and Dhalla (1989) state “...oxidation products of catecholamines, such as adrenochrome, rather than catecholamines per se, may be involved in catecholamine-induced myocardial cell damage. Previous studies have revealed that adrenochrome is capable of inducing coronary spasm, arrhythmias, ultrastructural changes and ventricular dysfunction.” They suggest damage caused by pheochromocytomas is due to adrenochrome. Extra adrenaline is oxidized when other mechanisms for inactivating catecholamines are saturated.

Colleague John Smythies reported in 2002 that there is evidence “...that the gene for the enzyme glutathioneS-transferase is defective in schizophrenics. This enzyme detoxifies adrenochrome” (doi: 10.1080/10298420290015827).

Trying to explain why the adrenochrome hypothesis and the orthomolecular approach to schizophrenia and other diseases was not explored by his contemporaries, Hoffer proposed another theory: “There is the enormous risk one might have to change one’s mind.”

As a biochemist studying niacin, Hoffer was familiar with the niacin deficiency disease pellagra. Known as having symptoms called “The 4 D’s”, diarrhea, dermatitis, dementia, and death, it is caused by a chronic dietary deficiency of the B vitamin niacin. Other factors may include tryptophan or lysine deficiency, or a leucine excess. Tryptophan, lysine, and leucine are essential amino acids.

brokenhearted

An excellent article by Alfred Jay Bollet, M.D. appearing in the Yale Journal of Biology and Medicine 65 (1992), 211-221, titled “Politics and Pellagra: The Epidemic of Pellagra in the U.S. in the Early Twentieth Century”, summarized here, refreshes our historical perspective on a serious disease and the politics of medicine.

A nutritional wasting disease, pellagra was epidemic in the United States in the early 20th century, especially in the southern states where corn was a staple food. A “First National Conference on Pellagra” in South Carolina in 1908 initiated the “pellagra scare” and “pellagraphobia”. Rarely observed in the U.S. prior to the early 1900’s, a precipitating factor in the epidemic was the mechanized degermination of corn by the Beall degerminator introduced during the first decade (Bollet). This new industrial method of degerminating corn, while increasing the stability of cornmeal for storage and transport, removed the corn germ, which contains enzymes, fats, and niacin, thus reducing its nutritional value. An analogous phenomenon caused the beriberi epidemic in Asia in the late 19th century: a new method of milling rice removed the husk, which contains the essential B vitamin thiamin. That milling process was intended to improve rice’s shelf life.

In fact, biochemical researcher Casimir Funk, who identified husk-milling as causal in thiamin deficiency beriberi, proposed in 1913 that the new corn milling technology affected its nutritional value and was responsible for pellagra. Unfortunately for the many people who later died from pellagra (conservatively estimated at 27,648 between 1915 and 1925; Bollet), Funk’s observation was ignored. The reason Funk’s observation, and that of others, was ignored provides a revealing look into the politics of medical science, then and now.

By 1912 Funk proposed that many common diseases blamed on infectious microorganisms or food intoxication were due to nutritional deficiencies. By this time, however, the magic bullet concept of Ehrlich and the germ theory of Koch had become very popular, obscuring the less exciting science of nutritional factors in food, factors necessary to prevent common diseases and promote health. This refusal to consider nutritional factors had dramatic consequences. By some estimates, between 1906 and 1940, which was the period of the epidemic, there were about 3,000,000 reported cases and 100,000 deaths due to pellagra. And these figures do not include statistics from 4 southern states whose officials refused to report but that were known to have had a high incidence of the disease (Bollet).

The rate at which pellagra became an epidemic convinced epidemiologists that an infectious agent was to blame. This idea was accepted readily by doctors and officials in the affected states whose view may have been obscured by cultural values. Considered a social stigma associated with poverty and race, the epidemic was an embarrassment to local politicians and an insult to “Southern pride”. Many doctors ignored the problem even when the Surgeon General of the Public Health Service declared that pellagra was becoming a “national calamity”. Assigned to finding the infectious agent and possibly its insect vector, a commission was established in South Carolina. Not surprisingly, the commission found no relationship between diet and the disease but identified unsanitary living conditions as the cause. “... it was more acceptable for it to be considered infectious than a direct result of poverty” (Bollet).

Joseph Goldberger, M.D., whose letter to the Surgeon General identified a relationship between poverty, poor diet, and pellagra, was appointed to study the epidemic in 1914. He had had significant experience in epidemiology but, an immigrant from New York, he did not receive the hospitality by which Southerners usually were known. Coupled with worsening economic conditions and still stinging from the loss of their agrarian lifestyle at the hands of the industrial North, Southerner’s sensibilities contributed to Goldberger’s uphill battle. On several occasions he demonstrated that pellagra could be reversed within days by feeding pellagrins a varied diet that included meat, milk, and fresh vegetables, and that the disease could be induced by feeding healthy subjects a restricted corn-based diet. Still, doctors were unimpressed. Goldberger died in 1927 before the anti-pellagra factor in food could be identified.

In 1937 nutritional biochemist C.A. Elvehjem at the Department of Agricultural Chemistry, University of Wisconsin, isolated from meat and yeast an antipellagra factor, which he called vitamin G in honor of Goldberger. In 1938 Tom Spies, M.D. identified the antipellagra factor as nicotinic acid, also called niacin and vitamin B-3. Spies received recognition from the American Medical Association for his nutritional research on pellagra and a disease called tropical sprue, which he treated successfully with the B vitamin folic acid.

In 1949 William Kaufman, M.D., Ph.D., published The Common Form of Joint Dysfunction based on his clinical studies with niacinamide deficiency disease, which he called “aniacinamidosis” and whose symptoms were similar to those of pellagra. Kaufman observed that patients with aniacinamidosis and arthritis responded to niacinamide therapy and regressed when niacinamide was removed from therapy.

In 1952, having earned a Ph.D. in biochemistry researching niacin in grains and an M.D. with an interest in psychosomatic medicine, Abram Hoffer, with Humphrey Osmond, M.D., began an investigation into schizophrenia. It is noteworthy that, according to Bollet, in 1906 a doctor in a mental hospital in Alabama identified 88 cases of pellagra “with a mortality rate of of 64 percent”. Orphanages, prisons, and mental hospitals seemed to have higher concentrations of people with the disease, though it was found also in the general population. Hoffer’s observations, that the hospitals and especially the mental hospitals in Canada in the early 1950’s, were highly populated with schizophrenics, echoes the 1906 observation. Moreover, though pellagra is associated with the “4 D’s”, Hoffer, as well as other doctors, suggest that the disease onset involves the nervous system, cognitive function, and emotional disturbances (aggressiveness, anxiety, ataxia, confusion, hypersensitivity, and so on). Certainly, poor nutrition is a predisposing factor for many diseases, including pellagra. However, it’s likely that many institutionalized people, in 1906 and today, suffer a “pre-pellagra” or a “non-dermatitis pellagra” even before being subjected to non-nutritious institution food. They will never recover from their B-3 “dependency” though their diets may provide enough nutritional factors to prevent the diagnosis of pellagra.

If vitamin B-3 is even moderately effective in treating aggression, anxiety, ataxia, and other nervous system symptoms of imbalance, we owe it to inmates in the overcrowded prisons and to the homeless people on the street to give it a try. Andrew Saul discusses vitamin B-3 for mental illness and other health problems on mercola.com, October 21, 2012.

... men’s hearts will fail from fear...

According to Decherd and Visscher, in 1927

Starling and Visscher found that adrenalin, although it caused a great increase in total energy liberation, produced a marked lowering of efficiency and therefore left the heart in worse condition than it had been before. Although temporarily stimulating to energy liberation by the heart, adrenalin eventually leaves the heart muscle less efficient and must therefore frequently be very harmful to a weakened myocardium.

In Circulation in 1986 (PMID3510777) an article titled “Milrinone for long-term therapy of severe heart failure…” researchers testing milrinone on subjects with severe heart failure found that 25 of 37 patients reported “substantial improvement in well-being”. However, 24 of the 37 subjects died, either of sudden death or worsening heart failure. And they report that “...long-term therapy with milrinone appears to improve functional status without eliciting overt clinical adverse reactions. However, the possibility that milrinone might have contributed to the high mortality noted during this therapeutic trial cannot be excluded.” In other words, it’s a good drug but may have death as a side effect.

A 1991 New England Journal of Medicine article detailing research in which patients with severe heart failure were administered milrinone (doi: 10.1056/NEJM199111213252103) concluded,

that despite its beneficial hemodynamic actions, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe chronic heart failure.

In this research, milrinone “was associated with a 28 percent increase in mortality from all causes”... and “...a 34 percent increase in cardiovascular mortality…” which increased to 53 percent for those “patients with the most severe symptoms”. Milrinone is still prescribed for patients diagnosed with heart failure in spite of this project’s findings that include no beneficial effects and “serious adverse cardiovascular reactions…”

In discussing heart muscle function, an inotrope is a substance that changes the force of the heart’s contraction. A positive inotrope, such as milrinone in the above research, increases the force of the heart’s contraction and in so doing increases intracellular calcium. Adrenalin, angiotensin, amrinone, and milrinone are among the positive cardiac inotropes. In spite of the Starling and Descher observation of the effect of adrenalin on heart muscle, the abstract of the milrinone study says “...the long-term effect of this type of positive inotropic agent on the survival of patients with chronic heart failure has not been determined.” However, a 1984 study of the positive inotrope amrinone concluded that “Prolonged administration of inotropic drugs may achieve short-term gains at the expense of long-term detrimental effects on the myocardium.”

Amrinone and milrinone are chemical analogs, the latter a derivative of the former, and belong to the class of positive inotropes whose action is to target and inhibit phosphodiesterase in the heart. Research on the effect of these drugs began in about 1980 shortly after drug company Sterling-Winthrop invented and patented amrinone. Numerous studies in the 1980’s, some supported by Sterling-Winthrop and mostly equivocal, found beneficial positive inotropic effects with amrinone and milrinone. One amrinone researcher who did not arrive at the conclusions favorable to Sterling-Winthrop, however, encountered resistance from the drug company and from within the profession, in general, when he tried to have his research published. British cardiologist Peter Wilmshurst, M.D. was ignored, threatened, and then censored when his research on amrinone did not match up to previous research and Sterling-Winthrop’s expectations. When he tried to publicise the “misconduct” in medical research that he’d discovered subsequently, he had difficulty finding someone to listen, including a high profile medical journal, industry regulators, and editors at the Guardian newspaper (healthwatch-uk.org).

In 1992 a review in Clinical Cardiology (16, 5-14) titled “Inotropic Therapy of the Failing Myocardium” summarized that “...the phosphodiesterase inhibitors - amrinone, milrinone, and enoximone - have demonstrated unacceptable clinical side effects and have been withdrawn from further clinical study.”

But in January 2015 researchers in China reported in Basic and Clinical Pharmacology and Toxicology the results of their meta analysis:

Despite advances in modern medicine, the treatment of acute heart failure (AHF) after acute myocardial infarction (AMI) remains challenging. Milrinone is effective in the treatment of chronic congestive heart failure, but its safety and efficacy in patients with AHF after AMI have not been systematically evaluated.

While studies to date are few and limited by small sample sizes and poor quality, they suggest that treatment with milrinone may be safe and effective for patients with AHF after AMI. However, this meta-analysis did not show that milrinone could improve prognosis or the survival rat.

Maybe someday the numbers will come out right.

my heart in my mouth

Adrenalin, an endogenous positive inotrope, is a biochemical mediator of the so-called “fight-or-flight” reaction. This automatic reaction is in response to a perceived threat to one’s being. The threat may or may not be “real”, but it often is accompanied by fear (Cognition & Emotion, Volume 13, Issue 2, 1999).

In response to the perceived threat, adrenalin is secreted by the adrenal medulla into the bloodstream. Some effects of this stimulation include increased heart rate, increased respiratory rate, increased blood pressure by constriction of blood vessels, an increase in blood fatty acids and glucose, and, as it increases sympathetic nervous system activity, a decrease in digestive and immune system functions. Strong sensory stimuli, such as loud noises and bright lights, also will cause an increased secretion of adrenalin.

Adrenalin is used medically to treat anaphylactic shock and cardiac arrest.

Positive inotropes adrenalin, milrinone, and amrinone do not have identical effects on the heart. A net effect of these substances, however, is the same: they increase the flow of calcium into heart muscle cells and thereby increase the heart’s contraction.

The adrenal glands are located on top of the kidneys. In addition to adrenalin, the adrenal glands produce cortisol and aldosterone (which has its effect on the kidneys and the cardiovascular system as noted above) and other steroidal hormones.

The “fight-or-flight” reaction was first identified by physiologist Walter Cannon in the early 20th century. Its effect is important for short-term survival when danger presents. But if the reaction is prolonged, or if it becomes chronic, and the body is not permitted to recover from its effects, the body’s resources will be depleted and it will be unable to carry out many of its normal functions. Hans Selye, M.D., in his 1956 classic The Stress of Life identified three phases of the human body’s response to stress, which he called the “general adaptation syndrome” (GAS): alarm, resistance, and exhaustion. The final phase of Selye’s GAS, exhaustion, may result in cardiovascular disease, compromised immune function, diabetes, gastrointestinal disturbances, kidney disease, and depression.

Selye suggested that we attend to our internal, physiological state to become more aware of how stress becomes distress, which may lead to exhaustion and disease. His list of signs of distress that are “self-observable” includes irritability, heart-pounding (indicative of high blood pressure), impulsive behavior, emotional instability, increased thirst, fatigue, insomnia, indigestion, and even neurosis or psychosis.

For a culture such as ours in which excitement, sensationalism, thrill-seeking, and the “adrenalin rush” are desirable indicators of “fun”, attentive self-modulation of the stress reaction may not be a popular activity. Considering that many of us have a low fight-or-flight threshold as it were built into our daily work and personal relationship activities, chances are the suggestion would be met with confusion - at best.

In 1975 Herbert Benson, M.D. published results of research that he describes as “...the opposite of the fight or flight response” in his book The Relaxation Response. Benson describes the Relaxation Response as “ a physical state of deep rest that changes the physical and emotional responses to stress.” In the introduction to the 2000 edition of the book Benson says,

Thirty-five years ago, when I was a young cardiologist, I noticed a trend among my patients with high blood pressure, or hypertension, a silent and dangerous precursor of heart disease. Once I prescribed medications, I noticed they often complained about fainting or becoming dizzy. These were side effects of having their blood pressures lowered with medications. Patients went from feeling fine to being burdened with irritating and disabling side effects, all the result of medicine I had prescribed.

This troubled me. It appeared that by following the standard treatment approach, I was over-medicating patients - unleashing on otherwise symptomless people maddening side effects from medications that they would be required to take the rest of their lives.

After being approached in the late 1960’s by Transcendental Meditation (TM) practitioners who said they could lower their blood pressure intentionally, Benson’s research uncovered the “Relaxation Response - an inducible, physiologic state of quietude.” The more he learned about adrenalin and stress the more he realized that they “...contributed to or caused many more medical problems than Western medicine appreciated.”

In modern times, the Relaxation Response is undoubtedly even more important to our survival, since anxiety and tension often inappropriately trigger the fight-or-flight response in us. Regular elicitation of the Relaxation Response can prevent, and compensate for, the damage incurred by frequent nervous reactions that pulse through our hearts and bodies.

Benson’s “Relaxation Response” is a generic Western interpretation of Eastern meditation techniques.

According to Hoffer, adrenochrome, the oxidized form of adrenalin, is toxic to the brain and heart. If more is made than can be metabolized serious brain dysfunction may result. Although adrenalin oxidizes to adrenochrome spontaneously, an enzyme that oxidizes adrenalin to adrenochrome is very high in heart tissue. Toxic to heart muscle, adrenochrome “...may be responsible for fibrillation and sudden death under stress” according to Hoffer. Since adrenochrome inhibits cellular respiration and niacin is necessary for many metabolic and cellular processes, Hoffer chose niacin over other B complex vitamins for his research. He observed that dementia in its early stages in pellagra resembled schizophrenia. He believed that niacin “...relieves the body of the pernicious effects of chronic stress…” and “...frees the body to carry on its routine function of repairing itself more efficiently. Vitamin B-3 is a specific antidote to adrenalin…” (Vitamin B-3: Niacin and Its Amide, by A. Hoffer, M.D., Ph.D., at doctoryourself.com).

the heart of the matter

The desperate disability of contemporary man to envisage an alternative to the industrial aggression on the human condition is an integral part of the curse from which he suffers. (Ivan Illich, “Medical Nemesis”, doi: 10.1136/jech.57.12.010; first published in 1974 in the Lancet).

Social philosopher and critic Ivan Illich wrote in 1974 that the

...technically unwarranted rise of medical prestige can only be explained as a magical ritual for the achievement of goals which are beyond technical and political reach.

Illich says that what he calls the “Medical Nemesis”, which he defines as “the backlash of progress” in medicine or the “inescapable cosmic retaliation” for an industrial medicine that has ignored its limitations, is difficult to verify or measure in a conventional way, but that the “...intensity with which it is experienced depends on the independence, vitality, and relatedness of each individual.” He says,

Within the last decade medical professional practice has become a major threat to health. Depression, infection, disability, dysfunction, and other specific iatrogenic diseases now cause more suffering than all accidents from traffic or industry. Beyond this, medical practice sponsors sickness by the reinforcement of a morbid society… the so-called health-professions have an indirect sickening power - a structurally health-denying effect.

Illich says that “Medical Nemesis” is an aspect of a more general phenomenon he calls “industrial Nemesis”, which is

the backlash of institutionally structured industrial hubris. This hubris consists of a disregard for the boundaries within which the human phenomenon remains viable. Current research is overwhelmingly oriented towards unattainable ‘breakthroughs’. What I have called counterfoil research is the disciplined analysis of the levels at which such reverberations must inevitably damage man.

The indictment of medicine as a form of institutional hubris exposes precisely those personal illusions which make the critic dependent on health care.

To the degree to which he becomes dependent on the management of his intimacy he renounces his autonomy and his health must decline.

That society which can reduce professional intervention to the minimum will provide the best conditions for health.

take it to heart

Dr. William Conder. February 2015.